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Verfasst von:Harnoß, Jonathan M. [VerfasserIn]   i
 Radhakrishnan, Praveen [VerfasserIn]   i
 Leowardi-Bauer, Christine [VerfasserIn]   i
 Strowitzki, Moritz [VerfasserIn]   i
 Schaible, Anja [VerfasserIn]   i
 Lasitschka, Felix [VerfasserIn]   i
 Schneider, Martin [VerfasserIn]   i
Titel:Prolyl hydroxylase inhibition Mitigates Pouchitis
Verf.angabe:Jonathan M. Harnoss, Jasper M. Gebhardt, Praveen Radhakrishnan, Christine Leowardi, Julius Burmeister, Doug N. Halligan, Shuai Yuan, Kilian B. Kennel, Moritz J. Strowitzki, Anja Schaible, Felix Lasitschka, Cormac T. Taylor, Martin Schneider
Jahr:2020
Umfang:14 S.
Teil:volume:26
 year:2020
 number:2
 pages:192-205
 extent:14
Fussnoten:Published online: 16 October 2019 ; Gesehen am 17.02.2020
Titel Quelle:Enthalten in: Inflammatory bowel diseases
Ort Quelle:Oxford : Oxford University Press, 1995
Jahr Quelle:2020
Band/Heft Quelle:26(2020), 2, Seite 192-205
ISSN Quelle:1536-4844
Abstract:Background: Pouchitis is the most common long-term complication after restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) for ulcerative colitis (UC) or familial adenomatous polyposis (FAP), which can eventually progress to pouch failure, necessitating permanent stoma construction. Hypoxia-inducible transcription factor prolyl hydroxylase–containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors that control adaptive gene expression through hypoxia-inducible factor (HIF). Emerging evidence supports PHDs as being therapeutic targets in intestinal inflammation. However, pharmacological inhibition of PHDs has not been validated as a treatment strategy in pouchitis. Methods: PHD1-3 mRNA and protein expression were analyzed in mucosal pouch and prepouch ileal patient biopsies. After establishment of a preclinical IPAA model in rats, the impact of the pan-PHD small-molecule inhibitor dimethyloxalylglycine (DMOG) on dextran sulfate sodium (DSS)–induced pouchitis was studied. Clinical and molecular parameters were investigated. Results: PHD1, but not PHD2 or PHD3, was overexpressed in pouchitis in biopsies of patients with IPAA for UC but not FAP. In addition, PHD1 expression correlated with disease activity. DMOG treatment profoundly mitigated DSS-induced pouchitis in a rodent IPAA model. Mechanistically, DMOG restored intestinal epithelial barrier function by induction of tight junction proteins zona occludens-1 and claudin-1 and alleviation of intestinal epithelial cell apoptosis, thus attenuating pouch inflammation. Conclusions: Together, these results establish a strong therapeutic rationale for targeting PHD1 with small-molecule inhibitors in pouchitis after IPAA for UC.
DOI:doi:10.1093/ibd/izz218
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext: https://doi.org/10.1093/ibd/izz218
 Verlag: https://academic.oup.com/ibdjournal/article/26/2/192/5588655
 DOI: https://doi.org/10.1093/ibd/izz218
Datenträger:Online-Ressource
Sprache:eng
K10plus-PPN:1690122749
Verknüpfungen:→ Zeitschrift

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